Liver sinusoidal endothelial cells phenotypes as early predictors of sepsis-associated liver dysfunction

Sepsis-associated liver dysfunction (SALD) is a common and prognostically relevant complication of critical illness, but its early detection remains challenging. We investigated whether circulating endothelial phenotyping could identify patients at risk of early SALD.

In this prospective, multicenter observational study, 214 adult postsurgical patients admitted to intensive care units at three Spanish hospitals were classified as critical controls (n = 77), sepsis (n = 61), or septic shock (n = 76) according to Sepsis-3 criteria. During the first 7 days after sepsis diagnosis, 42 patients developed SALD, defined by total serum bilirubin >2 mg/dL and international normalized ratio > 1.5. Peripheral blood mononuclear cells were analysed using high-dimensional spectral flow cytometry. Endothelial cells were defined as CD45^-/CD31⁺, and eight phenotypes were characterized within the CD32b⁺ compartment according to CD36, PV1, and HLA-DR expression. LASSO-Cox regression identified two populations, differing only in HLA-DR expression, and their ratio was subsequently evaluated as an endothelial marker.

Total endothelial cell counts did not differ significantly according to subsequent SALD development. A higher HLA-DR ratio was associated with increased SALD incidence (log-rank p = 0.00045) and remained independently associated after adjustment for age and baseline bilirubin. The HLA-DR ratio showed good discrimination for early SALD (AUC 0.802), compared with bilirubin alone (AUC 0.730).

Circulating endothelial phenotyping identifies a specific endothelial phenotype associated with subsequent SALD beyond total endothelial cell abundance and conventional bilirubin measurements. The HLA-DR ratio may provide complementary information for early risk stratification of SALD.

This study provides biological and clinical support for liver sinusoidal endothelial cells subset phenotyping as an early indicator of sepsis-associated liver dysfunction, addressing the limited sensitivity of conventional biochemical markers. The findings are particularly relevant for hepatologists and intensivists, as they identify an activated HLA-DR⁺ liver sinusoidal endothelial cells subset associated with subsequent liver dysfunction in critically ill patients. While further validation and methodological simplification are required, endothelial phenotyping could complement existing diagnostic approaches to improve early risk stratification in sepsis-related liver injury.